Clozapine Augmentation
Graylands Hospital Drug Bulletin 2004 Vol. 12 No. 1 March ISSN 1323-1251
Although clozapine is indicated for the
treatment of refractory schizophrenia, there will
still be a proportion of patients who will not
respond adequately at therapeutic doses. As
most patients on clozapine have no viable
monotherapy options left, one strategy that is
often explored is augmentation of clozapine
treatment with another agent.
The premise behind certain clozapine
augmentation strategies
Clozapine has a relatively low dopamine D2
receptor occupancy. Augmenting clozapine
with antipsychotics that have a higher affinity
for D2 receptors attempts to facilitate an
additive antipsychotic effect by covering a
larger range of receptor profiles. Increasing the
D2 receptor occupancy however, increases the
likelihood of a patient experiencing
extrapyramidal side effects and developing
tardive dyskinesia.
Another hypothesis that has been explored in
clozapine augmentation is the glutamate
hyperfunction hypothesis, which suggests that
patients with schizophrenia have dysfunctional
glutamatergic neuro-transmission. This has led
to trials investigating whether lamotrigine, a
glutamate excess release inhibitor, may be
effective in the augmentation of clozapine.
Other strategies involve the use of an agent,
which may interact with clozapine resulting in
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higher clozapine levels, such as risperidone or a
selective serotonin reuptake inhibitor (SSRI).
How this relates to clinical benefit as opposed to
just increasing the dose of clozapine is unclear.
Is there any evidence for augmentation?
In clinical practice, the use of combination
antipsychotics, including clozapine, is not
uncommon, however, there is limited
documentation on efficacy and safety of these
practices available in the current academic
literature.
There has only been one positive double-blind
randomised trial involving clozapine
augmentation with an antipsychotic. The
antipsychotic involved was sulpiride, which is
not available in Australia.
More research is required to establish the
efficacy and safety of the often expensive
clozapine augmentation strategies.
It is important to note that the addition of
another antipsychotic to an existing clozapine
regimen will increase the risk of a patient
developing agranulocytosis. This risk is further
complicated if the drug is given as a depot.
The following tables summarise the available
evidence found in various psychotropic texts,
journal articles and review articles relating to
clozapine augmentation efficacy and safety.
 ANTIPSYCHOTICS
OPTION EVIDENCE
1
RISPERIDONE One Single Blind Study
-
(1-6mg) All patients (N=40) in the study, randomised to
either clozapine/risperidone or clozapine
/placebo, showed clinical improvement by
BPRS (Brief Psychiatric Rating Scale) and
CGI(Clinical Global Impression), though
patients on risperidone combination had a
significantly greater improvement in BPRS.1
Three Open Trials2,3,4
- One 4 week trial (N=12) found no patients
responded to this combination2.
- One 12 week trial (N=13) found improvement
in 10 patients on this combination3.
- One 4 week trial (N=12) found significant
reduction in symptoms in 10 patients on this
combination4.
Twelve Case Reports5,6,7,8,9,10
- Ten of the case reports described improvement
in patients’ positive or positive and negative
symptoms on this combination.
OLANZAPINE Three Case reports19,20
(10-15mg/day) - Improvement in psychiatric symptoms was
seen in all three cases on a clozapine/
olanzapine combination.
AMISULPRIDE Three Open Trials23,24,25
(400-800mg) - In one trial (N=9) 6 patients showed clinical
improvement and 1 patient developed
agranulocytosis23.
- One trial (N=9) found all patients showed
clinical improvement24.
- One trial (N=5) found that adding amisulpride
to clozapine therapy increased the dopamine
D2 receptor occupancy. All patients showed
clinical improvement25.
QUETIAPINE One Retrospective Study26
(200-800mg) - Quetiapine was added to clozapine therapy in
65 treatment-responsive patients in an attempt
to limit the impact of clozapine on weight gain
and glycaemic control. It did not study the
effect of the combination on the symptoms of
schizophrenia.
SULPIRIDE One Double Blind Study (N=28)28
(400-600mg) - Significant improvements in positive and
negative symptoms were seen in the
clozapine/sulpiride group after 10 weeks.
One Open Trial29
- The 10 week open trial (N=6) found a
remarkable reduction in positive and negative
symptoms in 4 patients.
One Case Report30
- Marked benefit seen in a patient on clozapine
and sulpiride.
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COMMENTS
•
Risperidone may increase
plasma concentrations of
clozapine due to competitive
inhibition of the CYP2D6
enzyme11,12,13.
• This combination has been
shown in one study to result in
a moderate elevation of serum
prolactin levels and may
possibly affect a patient’s
weight and Body Mass Index
(BMI) more than the effect of
clozapine alone14.
• There have been single case
reports of arrhythmia15,
worsening of hoarding
behaviour16, agranulocytosis17
and a mild form of neuroleptic
malignant syndrome (NMS)18,
in patients on this combination.
• Inadequate evidence available
for this combination.
• Potential for significant weight
gain.
• Two reported cases of possible
NMS in patients receiving this
combination21,22.
• Very limited evidence available
at the moment to support the
use of this combination.
• No evidence from controlled
studies concerning risks and
benefits.
• There is a case report of
granulocytopenia with
clozapine and quetiapine27.
• The only antipsychotic
combination to be supported by
a randomised double blind trial.
• Sulpiride not available in
Australia
• The relationship between
sulpiride and amisulpride is
unclear.
 OPTIONS EVIDENCE COMMENTS
ARIPIPRAZOLE A new antipsychotic with no published information • Clinical trials required to
establish its effectiveness in
clozapine augmentation.
CHLORPROMAZINE One Double Blind Study31 • No evidence to suggest benefit.
( 100-400mg/day) - No significant differences between treatment • Agranulocytosis is listed as a
groups could be demonstrated. common adverse effect of
chlorpromazine. Combined use
with clozapine could increase
this risk and is best avoided.
HALOPERIDOL Two Case Studies32 • No evidence from controlled
(Doses not clear) - Both patients showed significant improvement. studies concerning risks and
benefits.
FLUPHENAZINE One Case Study32 • No evidence from controlled
(Dose not clear) - Patient showed significant improvement. studies concerning risks and
benefits.
PIMOZIDE One Retrospective Study33 • No evidence from controlled
(2-8mg/day) - All patients in study (N=7) had clinical studies concerning risks and
improvement on this combination benefits.
• Pimozide can cause prolonged
QT interval, arrhythmias and
ECG changes. Combined use
with clozapine may increase
incidence of cardiac side effects.

MOOD-STABILISERS
OPTION EVIDENCE COMMENTS
LAMOTRIGINE One Double Blind Study34 • Promising evidence that this
(25-250mg/day) - Lamotrigine with clozapine was more effective combination may be useful in
in reducing positive symptoms than placebo partial or non-responders to
with clozapine. No effect on negative clozapine.
symptoms. (N=16) • There is one case report of
Two Open Trials35,36 lamotrigine causing elevated
- Both trials (N=6 and N=17) found significant clozapine levels, with no clinical
improvement in all patients on combination35,36. improvement in patient39.
Four Case Studies37,38
- 3 cases showed significant decrease in BPRS in
patients on this combination37, while another
case saw improvement in a bipolar patient38.
VALPROATE One Retrospective Study40 • No evidence from controlled
(Doses not clarified) - The combination was efficacious and well studies to suggest benefit.
tolerated in the majority of patients (N=55) • Potential for significant weight
gain.
• Case reports of oversedation41,
increased risk of neutropenia and
agranulocytosis42, hepatic
encephalopathy43 and small
increases in plasma
concentrations of clozapine44, in
patients on this combination.
CARBAMAZEPINE No information found • No evidence at all to suggest a
benefit.
• Carbamazepine can decrease
clozapine levels45,46.
• Combination is best avoided as
increases risk of serious
haematological adverse effects.

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 OPTION EVIDENCE COMMENTS
•
47
LITHIUM One Randomised Controlled Trial(N=20) Limited evidence available to
(Commenced on - Improvement in 10 patients with suggest benefit.
600mg/day, adjusted schizoaffective disorder, though no • Case reports of reversible
according to lithium improvement in 10 patients with neurotoxicity48, diabetic
levels) schizophrenia on this combination. ketoacidosis49,50, seizures51 and
apparent NMS52 with this
combination.
TOPIRAMATE Two Open Trials36,53 • Although it has been suggested
(200-300mg/day) - No significant improvement seen in any that topiramate may induce
patients on this combination (N=9) in one weight loss in clozapine
trial36, while deterioration was seen in all patients, it appears that it may
patients in the other trial (N=4)53. actually worsen psychosis and
One Case Study54 should be used with caution.
- Worsening of psychosis on this
combination.
GABAPENTIN No information found • No evidence at all to suggest a
benefit.

OTHERS

OPTION EVIDENCE AND COMMENTS

SELECTIVE SEROTONIN
REUPTAKE INHIBITORS
(SSRIs)
ELECTROCONVULSIVE
THERAPY (ECT)
FISH OIL
(1-4g Eicosapentaenoic
Acid [EPA]. Each 1g fish
oil capsule contains approx
180mg EPA depending on
brand)
• Only one double-blind controlled trial with an SSRI (fluoxetine) was found. It
found this combination had no significant improvement in psychotic symptoms55.
• There are case reports regarding fluoxetine, fluvoxamine, sertraline and
paroxetine with some citing clinical improvement, some no improvement and
others reported adverse effects56,57,58,59,60.
• SSRIs can interact with clozapine to increase clozapine levels. Citalopram
appears the least likely to do so, and fluvoxamine the most likely to do so. This
interaction is sometimes utilised to increase clozapine levels to give a greater
therapeutic response. How this equates to clinical benefit as opposed to just
increasing the dose of clozapine needs to be clarified.
• Although rare, SSRIs can also cause blood dyscrasias.
• There is limited evidence to support using SSRIs for augmentation of clozapine
and care should be taken due to their potential to increase clozapine levels.
• The use of ECT with clozapine is not contraindicated, however caution must be
taken as clozapine lowers the seizure threshold in a dose-dependent manner.
• No controlled studies concerning risks and benefits have been carried out.
• One retrospective study found 67% of patients reviewed (N=36) benefited from
combined clozapine and ECT treatment61. Another retrospective study (N=7)
found a 27% improvement in total BPRS62.
• There have also been a few case reports of clinical improvement in patients
receiving both clozapine and ECT63,64,65, although improvement may not
necessarily be sustained65.
• Case reports and prospective trials suggest possible benefit in schizophrenia,
including patients on clozapine, a summary of which can be found in Maudsley
prescribing guidelines66.

References available on request

Acknowledgement
This article was prepared by Anouska Feszczur and reviewed by members of the Pharmacy Department.
Comments are welcome at the email address: Druginformation.Graylands@health.wa.gov.au

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